Role of GATA-3 in Allergic Diseases

Peter   J.   Barnes

Abstract

GATA-3 is a transcription factor that is specifically expressed in T helper 2 (Th2) cells and plays a critical role in the differentiation of Th2 cells from uncommitted CD4+ lymphocytes. In addition GATA-3 is essential for the gene expression of the cytokines IL-4, IL-5 and IL-13 that mediate allergic inflammation. In human T lymphocytes GATA-3 is normally localized to the cytoplasm, but on activation by antigen-presenting cells via the T cell receptor (CD3) and co-stimulatory receptor CD28 GATA-3 is phosphorylated by p38 MAP kinase and translocates to the nucleus via the nuclear import protein importin-α. Corticosteroids bound to glucocorticoid receptors inhibit GATA-3 function by competing for nuclear entry via importin-α and also by inhibiting p38 MAP kinase through the induction of MAP kinase phosphatase-1. GATA-3 is inhibited by the Th1 master regulatory transcription T-bet but in turn inhibits STAT-4 and thus T-bet so that Th2 polarization is maintained. Since GATA-3 appears to be a critical transcription factor for allergic inflammation it is an obvious target for inhibition. However, direct inhibition by inhaled specific oligonucleotides or interference RNA is not yet possible. Corticosteroids act as indirect inhibitors and in patients with corticosteroid resistance p38 MAP kinase inhibitors may also prove to be useful in the future.

Keywords: Th2 cell, asthma, T-bet, IL-4, IL-5, IL-13, p38 MAP kinase, corticosteroids